Sirolimus damages podocytes in rats with protein overload nephropathy.

Abstract

BACKGROUND:

Conversion from calcineurin inhibitors (CNIs) to sirolimus could significantly improve long-term graft survival after kidney transplantation. Proteinuria was found in some recipients after the switch, which could be alleviated by an angiotensin II receptor blocker (ARB). But the mechanisms for this have remained unclear. In this study, we utilized a rat model with protein overload nephropathy to explore the mechanisms of sirolimus-related proteinuria.

METHODS:

A rat model with protein overload nephropathy was induced by repeated injections of bovine serum albumin. Model rats also received sirolimus (rapamycin) treatment or ARB agent (losartan) pretreatment. Urinary protein excretion from 24-hour urine specimens was calculated, and the morphological changes of renal tissues were analyzed by hematoxylin and eosin staining and electron microscopy. The expression of desmin, a sensitive marker of podocyte injury, was detected by immunohistochemical staining.

RESULTS:

Rapamycin increased urinary protein excretion and intratubular protein cast formation in rats with protein overload nephropathy. The foot process effacement of podocytes was found by electron microscopy after rapamycin treatment. The expression of desmin was up-regulated after rapamycin treatment. However, losartan pretreatment could attenuate proteinuria in spite of rapamycin treatment.

CONCLUSION:

Sirolimus aggravates proteinuria in rats with protein overload nephropathy by damaging podocytes, a barrier of glomerular filtration. Furthermore, angiotensin II receptor blocker can counteract the effect of sirolimus, not only through hemodynamic changes but also partly by repairing the injury of podocytes. This study might be useful for understanding the mechanism of sirolimus-related proteinuria and guiding clinical treatments.

• Authors: Yong Cai, Yan Chen, Shaoling Zheng, Bicheng Chen, Yirong Yang, Peng Xia
• Journal: Journal of nephrology (J Nephrol) 2011 May-Jun Vol. 24 Issue 3 Pg. 307-12 ISSN: 1724-6059 [Electronic] Italy
• PMID: 20954132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Biomarkers
• Desmin
• Immunosuppressive Agents
• Losartan
• Sirolimus

Topics

• Angiotensin II Type 1 Receptor Blockers (pharmacology, therapeutic use)
• Animals
• Biomarkers (metabolism)
• Desmin (metabolism)
• Disease Models, Animal
• Female
• Immunosuppressive Agents (adverse effects, pharmacology)
• Kidney Transplantation (immunology)
• Losartan (pharmacology, therapeutic use)
• Podocytes (drug effects, metabolism, pathology)
• Proteinuria (chemically induced, pathology, prevention & control)
• Rats
• Rats, Wistar
• Sirolimus (adverse effects, pharmacology)
• Up-Regulation